The Core continues to be a part of the Metabolic Clinical Research Unit (MCRU), which was established at NIH in 2007 under the first NIH Strategic Plan for Obesity Research (http://www.obesityresearch.nih.gov/strategic-plan). It is design to conduct research to identify potential causes and evaluate treatments of obesity. Currently 1/3 of the adult US population is obese and another 1/3 are overweight. Obesity is a major cause of diabetes, cardiovascular disease, and some cancers, yet our understanding of obesity physiology is rudimentary. The obesity epidemic has continued unabatedthe need for rigorous and properly controlled metabolic research is even more important. At the NIH, much of the Intramural clinical research is conducted on the MCRU that consists of the 5SW-N (inpatient) unit, 5SW-S (day hospital), and 7SW-S whole room calorimetry suites, which includes a special room with a DXA body composition scanner, and Bod Pod, an exercise testing room, portable activity measurements, and highlighted by the three customized whole-room indirect calorimeters (respiratory chambers) as the key components of the Core function. Despite of the Clinical Centers decision to reduce the 5SW-N inpatient unit from 10 to 7 rooms at the beginning of FY19, we actually increased our census and the services rendered: energy expenditure by respiratory chambers (383), resting energy expenditure by metabolic carts (551), graded-exercise tests (78), experimental food behavior tests (677), and body composition (233 DXA, 51 Bod Pod). The Core continues to support 29 clinical protocols and protocols from 14 different IC's of the NIH. Research highlights in FY19: 1. With Dr. Kevin Hall, we investigated whether ultra-processed foods affect energy intake in 20 weight-stable young to middle-aged adults. Subjects were randomized to receive either ultra-processed or unprocessed diets for 2 weeks immediately followed by the alternate diet for 2 weeks as inpatients on our Unit. Meals were designed to be matched for presented calories, energy density, macronutrients, sugar, sodium, and fiber. Subjects were instructed to consume as much or as little as desired. Energy intake was greater during the ultra-processed diet (508 106 kcal/day; p = 0.0001), with increased consumption of carbohydrate (280 54 kcal/day; p < 0.0001) and fat (230 53 kcal/day; p = 0.0004), but not protein (-2 12 kcal/day; p = 0.85). Weight changes were highly correlated with energy intake (r = 0.8, p < 0.0001), with participants gaining 0.9 0.3 kg (p = 0.009) during the ultra-processed diet and losing 0.9 0.3 kg (p = 0.007) during the unprocessed diet. The data suggest that limiting consumption of ultra-processed foods, as least in the short-term, may be an effective strategy for obesity prevention and treatment. 2. Using data we collected from a multi-center trial with Pennington Biomedical Research Center, Columbia University, the Translational Research Institute for Metabolism and Diabetes, we examined energy expenditure differences between isocaloric diets varying widely in carbohydrate (4 weeks inpatient with isocaloric ketogenic diet, KD, or baseline diet BD) and to quantitatively compare DLW data with respiratory chamber and body composition measurements within an energy balance framework. Neither chamber EE nor EE using energy balance (controlled intake and body composition) were different between KD and BD, but DLW EE was 209 83 kcal/d higher during the KD (P = 0.023) but was not significantly increased when adjusted for energy balance (EEDLWRQ = 139 89 kcal/d; P = 0.14). The data suggest that DLW calculations failing to account for diet-specific energy imbalance effects on RQ erroneously suggest that low-carbohydrate diets substantially increase energy expenditure. 3. We have been studying childhood obesity since the establishment of the Core. We continue to contribute to the studies with Dr. Jack Yanovskis research group from NICHD. In several recent papers, we sought to determine the relationship of physical fitness with two developmental phenomena of adolescence, insulin resistance and depression/anxiety symptoms among at-risk youth. We analyzed data from 241 overweight or obese adolescents (1217 years) from two studies conducted on our Unit. Insulin sensitivity (oral glucose tolerance test) was positively associated with fitness by walk/run distance (p<0.01), even after accounting for all covariates. Self-reported anxiety symptoms were inversely related to perceived exertion (p<0.05), adjusting for covariates. These findings suggest that insulin resistance and anxiety symptoms are associated with different dimensions of physical fitness in overweight or obese adolescents and could both potentially contribute to declining fitness and worsening metabolic outcomes in at-risk youth. 4. We also supported Drs. Andrew Demidowich and Jack Yanovski in a pilot randomized controlled trial to evaluate the efficacy and safety of colchicine (0.6 mg vs. placebo for 3 months) for improving metabolic and inflammatory outcomes in people with obesity and metabolic syndrome (MetS). Of 40 adult study participants randomized, 37 completed the trial. We found colchicine significantly improved obesity-associated inflammatory variables and showed a good safety profile among adults with obesity and MetS who did not have diabetes. These results suggest a larger, adequately powered study should be conducted to determine whether colchicine improves insulin resistance and other measures of metabolic health in at-risk individuals. 5. We collaborated in a NHGRI clinical trial in treating patients with PIK3CA-related overgrowth spectrum (PROS) with an mTOR inhibitor sirolimus. Thirty-nine patients with confirmed PROS and progressive overgrowth were enrolled into open-label studies across three centers. The a priori primary outcome was affected vs unaffected regional body composition changes assessed using dual energy X-ray absorptiometry during 26 weeks of untreated run-in and 26 weeks of sirolimus therapy. Thirty participants completed the study. Sirolimus led to a change in mean percentage total tissue volume of -7.2% (p=0.04) at affected sites, but not at unaffected sites (+1.7%, p=0.48). This study suggests that low-dose sirolimus can modestly reduce overgrowth, but cautions that the side-effect profile is significant, mandating individualized risk-benefit evaluations for sirolimus treatment in PROS.